The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists, processes for preparing them and their use in the treatment of respiratory diseases.
The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists, processes for preparing them and their use in the treatment of respiratory diseases.
Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory and/or obstructive diseases of the respiratory tract if one or more, preferably one, anticholinergic is used with one or more, preferably one, NK1-receptor antagonist. In view of this synergistic effect the pharmaceutical combinations according to the invention can be used in smaller doses than would be the case with the individual compounds used in monotherapy in the usual way.
The combinations of active substances according to the invention are surprisingly also characterised by a rapid onset of activity and also by a long-lasting effect. This is of great importance to the wellbeing of the patient as on the one hand he experiences a rapid improvement in his condition after the combination has been administered and also thanks to the long-lasting effect it is sufficient to take the drug once a day. The effects mentioned above may be observed both when the two active substances are administered simultaneously in a single active substance formulation and when they are administered successively in separate formulations. According to the invention, it is preferable to administer the two active substance ingredients simultaneously in a single formulation.
Within the scope of the present invention the term anticholinergics 1 denotes salts which are preferably selected from among tiotropium salts, oxitropium salts and ipratropium salts, most preferably ipratropium salts and tiotropium salts. In the above-mentioned salts the cations tiotropium, oxitropium and ipratropium are the pharmacologically active ingredients. Within the scope of the present patent application, any reference to the above cations is indicated by the use of the number 1xe2x80x2. Any reference to compounds 1 naturally also includes a reference to the ingredients 1xe2x80x2 (tiotropium, oxitropium or ipratropium).
By the salts 1 which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium, oxitropium or ipratropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate or para-toluenesulphonate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the salts 1, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention are salts 1 selected from among tiotropium bromide, oxitropium bromide and ipratropium bromide. Tiotropium bromide is particularly preferred.
Within the scope of the present invention, the word NK1-receptor antagonists (hereinafter 2) denotes compounds selected from among N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-cyclopropylmethyl-piperazin-1-yl}-N-methyl-2-phenyl-acetamide (BIIF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968(Saredutant), SR 140333 (Nolpitantium besilate/chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, Aprepitant (MK-869), L-754030, CJ-11974, L-758298, DNK-33A, 6b-I, CJ-11974, TAK-637, GR 205171 and the arylglycinamide derivatives of general formula 3
wherein
R1 and R2 together with the N to which they are bound form a ring of formula 
xe2x80x83wherein r and s are 2 or 3;
R6 denotes H, xe2x80x94C1-C5-alkyl, C3-C5-alkenyl, propynyl, hydroxy(C2-C4)alkyl, methoxy(C2-C4)alkyl, di(C1-C3)alkylamino(C2-C4)alkyl, amino(C2-C4)alkyl, amino, di(C1-C3)alkylamino, monofluoro to perfluoro(C1-C2)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
R7 has one of the meanings (a) to (d),
(a) hydroxy
(b) 4-piperidinopiperidyl, 
xe2x80x83wherein R16 and R17 independently of each other denote H, (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy(C2-C4)alkyl, dihydroxy(C2-C4)alkyl, (C1-C3)alkoxy(C2-C4)alkyl, phenyl(C1-C4)alkyl or di(C1-C3)alkylamino(C2-C4)alkyl,
R8 denotes H,
optionally in the form of the enantiomers and mixtures of enantiomers thereof, optionally in the form of the racemates thereof.
The abovementioned compounds of formula 3 are known for example from International Patent Applications WO 96/32386 and WO 97/32865, to which reference is hereby made in their entirety.
Preferably, the compound 2 is selected from among BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171 and the arylglycinamide derivatives of general formula 3, wherein
R1 and R2 together with the N to which they are bound form a ring of formula 
xe2x80x83wherein s is 2 or 3;
R7 denotes a group 
xe2x80x83wherein R16 and R17 independently of each other denote H, (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy(C2-C4)alkyl, dihydroxy(C2-C4)alkyl, (C1-C3)alkoxy(C2-C4)alkyl, phenyl(C1-C4)alkyl or di(C1-C3)alkylamino(C2-C4)alkyl,
R8 denotes H,
optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.
Particularly preferably, the compound 2 is selected from among BIIF1149 and the arylglycinamide derivatives of general formula 3, wherein
R1 and R2 together with the N to which they are bound form a ring of formula 
xe2x80x83wherein s is 2 and
R7 denotes a group 
xe2x80x83wherein R16 and R17 independently of each other denote H, (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy(C2-C4)alkyl or dihydroxy(C2-C4)alkyl,
R8 denotes H, optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.
Most particularly preferred as compounds of formula 2 are N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.
Of particular importance is N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, optionally in the form of its enantiomers, preferably in the form of its (S)-enantiomer, optionally in the form of the mixtures of enantiomers thereof, and optionally in the form of the racemates thereof.
Examples of alkyl groups (including those which are part of other groups), unless otherwise defined, are branched and unbranched alkyl groups with 1 to 5 carbon atoms, such as, for example: methyl, ethyl, propyl, 1-methylethyl(isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl(tert.butyl), etc. The definitions propyl, butyl and pentyl always include the associated isomeric groups. Hydroxy or dihydroxyalkyl groups are alkyl groups substituted by one or two hydroxy groups.
Examples of alkenyl groups (including those which are part of other groups) are branched and unbranched alkenyl groups with 3 to 5 carbon atoms, provided that they have at least one double bond, such as, for example, propenyl, isopropenyl, butenyl, etc.
Cycloalkyl generally denotes a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, etc.
Alkyloxy, which may optionally also be referred to as alkoxy, denotes a straight-chain or branched alkyl group bound via an oxygen atom. The methoxy group is particularly preferred.
Any reference to the abovementioned NK1-receptor antagonists 2 within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts thereof which may exist.
By the physiologically acceptable acid addition salts which may be formed from 2 are meant, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Particularly preferred salts of the compounds 2 according to the invention are those selected from among the acetate, hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate.
The pharmaceutical combinations of 1 and 2 according to the invention are preferably administered by inhalation. Suitable inhalable powders packed into suitable capsules (inhalettes) may be administered using suitable powder inhalers. Alternatively, the drug may be inhaled by the application of suitable inhalation aerosols. These also include powdered inhalation aerosols which contain for example HFA134a, HFA227 or a mixture thereof as propellant gas. The drug may also be inhaled using suitable solutions of the pharmaceutical combination consisting of 1 and 2.
In one aspect, therefore, the invention relates to a pharmaceutical composition which contains a combination of 1 and 2.
In another aspect the present invention relates to a pharmaceutical composition which contains one or more salts 1 and one or more compounds 2, optionally in the form of their solvates or hydrates. Again, the active substances may be combined in a single preparation or contained in two separate formulations. Pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred according to the invention.
In another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable carrier or excipient. In another aspect the present invention relates to a pharmaceutical composition which does not contain any pharmaceutically acceptable carrier or excipient in addition to therapeutically effective quantities of 1 and 2.
The present invention also relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective quantities of 1 and 2 for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD), and complications thereof such as pulmonary hypertension, as well as allergic and non-allergic rhinitis, provided that treatment with NK1-receptor antagonists is not contraindicated from a therapeutic point of view, by simultaneous or successive administration.
The present invention also relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions 1 and 2 for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD), and complications thereof such as pulmonary hypertension, as well as allergic and non-allergic rhinitis, provided that treatment with NK1-receptor antagonists is not contraindicated from a therapeutic point of view, by simultaneous or successive administration.
In the active substance combinations of 1 and 2 according to the invention, ingredients 1 and 2 may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.
The proportions in which the two active substances 1 and 2 may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2 in ratios by weight ranging from 1:300 to 50:1, preferably from 1:250 to 40:1. In the particularly preferred pharmaceutical combinations which contain tiotropium salt as compound 1 and a compound selected from among BIIF 1149, CGP 60829, MK-869, CJ-11974, GR 205171, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and the arylglycinamide derivatives of formula 3 as NK1-receptor antagonist 2, the weight ratios of 1 to 2 are most preferably in a range in which tiotropium 1xe2x80x2 and 2 are present in proportions of 1:150 to 30:1, more preferably from 1:50 to 20:1.
For example, without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain tiotropium 1xe2x80x2 and NK1-receptor antagonist 2 in the following weight ratios:
1:80, 1:79, 1:78, 1:77, 1:76, 1:75, 1:74, 1:73, 1:72, 1:71, 1:70, 1:69, 1:68, 1:67, 1:66, 1:65, 1:64, 1:63, 1:62, 1:61, 1:60, 1:59, 1:58, 1:57, 1:56, 1:55, 1:54, 1:53, 1:52, 1:51, 1:50; 1:49; 1:48; 1:47; 1:46; 1:45; 1:44; 1:43; 1:42; 1:41; 1:40; 1:39; 1:38; 1:37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27; 1:26; 1:25; 1:24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13; 1:12; 1:11; 1:10; 1:9; 1:8; 1:7; 1:6; 1:5; 1:4; 1:3; 1:2; 1:1; 2:1; 3:1; 4:1; 5:1; 6:1; 7:1; 8:1; 9:1; 10:1; 11:1; 12:1; 13:1; 14:1; 15:1; 16:1; 17:1; 18:1; 19:1; 20:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally administered so that 1 and 2 are present together in doses of 0.01 to 10000 xcexcg, preferably from 0.1 to 2000 xcexcg, more preferably from 1 to 1500 xcexcg, better still from 50 to 1200 xcexcg per single dose. For example, combinations of 1 and 2 according to the invention contain a quantity of tiotropium 1xe2x80x2 and NK1-receptor antagonist 2 such that the total dosage per single dose is about 100 xcexcg, 105 xcexcg, 110 xcexcg, 115 xcexcg, 120 xcexcg, 125 xcexcg, 130 xcexcg, 135 xcexcg, 140 xcexcg, 145 xcexcg, 150 xcexcg, 155 xcexcg, 160 xcexcg, 165 xcexcg, 170 xcexcg, 175 xcexcg, 180 xcexcg, 185 xcexcg, 190 xcexcg, 195 xcexcg, 200 xcexcg, 205 xcexcg, 210 xcexcg, 215 xcexcg, 220 xcexcg, 225 xcexcg, 230 xcexcg, 235 xcexcg, 240 xcexcg, 245 xcexcg, 250 xcexcg, 255 xcexcg, 260 xcexcg, 265 xcexcg, 270 xcexcg, 275 xcexcg, 280 xcexcg, 285 xcexcg, 290 xcexcg, 295 xcexcg, 300 xcexcg, 305 xcexcg, 310 xcexcg, 315 xcexcg, 320 xcexcg, 325 xcexcg, 330 xcexcg, 335 xcexcg, 340 xcexcg, 345 xcexcg, 350 xcexcg, 355 xcexcg, 360 xcexcg, 365 xcexcg, 370 xcexcg, 375 xcexcg, 380 xcexcg, 385 xcexcg, 390 xcexcg, 395 xcexcg, 400 xcexcg, 405 xcexcg, 410 xcexcg, 415 xcexcg, 420 xcexcg, 425 xcexcg, 430 xcexcg, 435 xcexcg, 440 xcexcg, 445 xcexcg, 450 xcexcg, 455 xcexcg, 460 xcexcg, 465 xcexcg, 470 xcexcg, 475 xcexcg, 480 xcexcg, 485 xcexcg, 490 xcexcg, 495 xcexcg, 500 xcexcg, 505 xcexcg, 510 xcexcg, 515 xcexcg, 520 xcexcg, 525 xcexcg, 530 xcexcg, 535 xcexcg, 540 xcexcg, 545 xcexcg, 550 xcexcg, 555 xcexcg, 560 xcexcg, 565 xcexcg, 570 xcexcg, 575 xcexcg, 580 xcexcg, 585 xcexcg, 590 xcexcg, 595 xcexcg, 600 xcexcg, 605 xcexcg, 610 xcexcg, 615 xcexcg, 620 xcexcg, 625 xcexcg, 630 xcexcg, 635 xcexcg, 640 xcexcg, 645 xcexcg, 650 xcexcg, 655 xcexcg, 660 xcexcg, 665 xcexcg, 670 xcexcg, 675 xcexcg, 680 xcexcg, 685 xcexcg, 690 xcexcg, 695 xcexcg, 700 xcexcg, 705 xcexcg, 710 xcexcg, 715 xcexcg, 720 xcexcg, 725 xcexcg, 730 xcexcg, 735 xcexcg, 740 xcexcg, 745 xcexcg, 750 xcexcg, 755 xcexcg, 760 xcexcg, 765 xcexcg, 770 xcexcg, 775 xcexcg, 780 xcexcg, 785 xcexcg, 790 xcexcg, 795 xcexcg, 800 xcexcg, 805 xcexcg, 810 xcexcg, 815 xcexcg, 820 xcexcg, 825 xcexcg, 830 xcexcg, 835 xcexcg, 840 xcexcg, 845 xcexcg, 850 xcexcg, 855 xcexcg, 860 xcexcg, 865 xcexcg, 870 xcexcg, 875 xcexcg, 880 xcexcg, 885 xcexcg, 890 xcexcg, 895 xcexcg, 900 xcexcg, 905 xcexcg, 910 xcexcg, 915 xcexcg, 920 xcexcg, 925 xcexcg, 930 xcexcg, 935 xcexcg, 940 xcexcg, 945 xcexcg, 950 xcexcg, 955 xcexcg, 960 xcexcg, 965 xcexcg, 970 xcexcg, 975 xcexcg, 980 xcexcg, 985 xcexcg, 990 xcexcg, 995 xcexcg, 1000 xcexcg, 1005 xcexcg, 1010 xcexcg, 1015 xcexcg, 1020 xcexcg, 1025 xcexcg, 1030 xcexcg, 1035 xcexcg, 1040 xcexcg, 1045 xcexcg, 1050 xcexcg, 1055 xcexcg, 1060 xcexcg, 1065 xcexcg, 1070 xcexcg, 1075 xcexcg, 1080 xcexcg, 1085 xcexcg, 1090 xcexcg, 1095 xcexcg, 1100 xcexcg or similar. The suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated, but are intended as dosages which are disclosed by way of example. Of course, dosages which may fluctuate about the abovementioned numerical values within a range of about +/xe2x88x922.5 xcexcg are also included in the values given above by way of example. In these dosage ranges, the active substances 1xe2x80x2 and 2 may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain a quantity of tiotropium 1xe2x80x2 and NK1-receptor antagonist 2 such that, for each single dose, 5 xcexcg of 1xe2x80x2 and 25 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 100 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 200 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 300 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 400 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 500 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 600 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 700 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 800 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 900 xcexcg of 2, 5 xcexcg of 1xe2x80x2 and 1000 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 25 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 100 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 200 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 300 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 400 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 500 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 600 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 700 xcexcg of 1, 10 xcexcg of 1xe2x80x2 and 800 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 900 xcexcg of 2, 10 xcexcg of 1xe2x80x2 and 1000 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 25 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 100 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 200 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 300 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 400 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 500 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 600 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 700 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 800 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 900 xcexcg of 2, 18 xcexcg of 1xe2x80x2 and 1000 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 25 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 100 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 200 xcexcg of 2, 2 xcexcg of 1xe2x80x2 and 300 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 400 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 500 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 600 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 700 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 800 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 900 xcexcg of 2, 20 xcexcg of 1xe2x80x2 and 1000 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 25 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 100 xcexcg of 1, 36 xcexcg of 1xe2x80x2 and 200 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 300 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 400 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 500 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 600 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 700 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 800 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 900 xcexcg of 2, 36 xcexcg of 1xe2x80x2 and 1000 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 25 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 50 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 100 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 200 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 300 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 400 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 500 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 600 xcexcg of 2, or 40 xcexcg of 1xe2x80x2 and 700 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 800 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 900 xcexcg of 2, 40 xcexcg of 1xe2x80x2 and 1000 xcexcg of 2, are administered.
If the active substance combination in which 1 denotes tiotropium bromide is used as the preferred combination of 1 and 2 according to the invention, the quantities of active substance 1xe2x80x2 and 2 administered per single dose mentioned by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6 xcexcg of 1 and 25 xcexcg of 2, 6 xcexcg of 1 and 50 xcexcg of 2, 6 xcexcg of 1 and 100 xcexcg of 2, 6 xcexcg of 1 and 200 xcexcg of 2, 6 xcexcg of 1 and 300 xcexcg of 2, 6 xcexcg of 1 and 400 xcexcg of 2, 6 xcexcg of 1 and 500 xcexcg of 2, 6 xcexcg of 1 and 600 xcexcg of 2, 6 xcexcg of 1 and 700 xcexcg of 2, 6 xcexcg of 1 and 800 xcexcg of 2, 6 xcexcg of 1 and 900 xcexcg of 2, 6 xcexcg of 1 and 1000 xcexcg of 2, 12 xcexcg of 1 and 25 xcexcg of 2, 12 xcexcg of 1 and 50 xcexcg of 2, 12 xcexcg of 1 and 100 xcexcg of 2, 12 xcexcg of 1 and 200 xcexcg of 2, 12 xcexcg of 1 and 300 xcexcg of 2, 12 xcexcg of 1 and 400 xcexcg of 2, 12 xcexcg of 1 and 500 xcexcg of 2, 12 xcexcg of 1 and 600 xcexcg of 2, 12 xcexcg of 1 and 700 xcexcg of 2, 12 xcexcg of 1 and 800 xcexcg of 2, 12 xcexcg of 1 and 900 xcexcg of 2, 12 xcexcg of 1 and 1000 xcexcg of 2, 21.7 xcexcg of 1 and 25 xcexcg of 2, 21.7 xcexcg of 1 and 50 xcexcg of 2, 21.7 xcexcg of 1 and 100 xcexcg of 2, 21.7 xcexcg of 1 and 200 xcexcg of 2, 21.7 xcexcg of 1 and 300 xcexcg of 2, 21.7 xcexcg of 1 and 400 xcexcg of 2, 21.7 xcexcg of 1 and 500 xcexcg of 2, 21.7 xcexcg of 1 and 600 xcexcg of 2, 21.7 xcexcg of 1 and 700 xcexcg of 2, 21.7 xcexcg of 1 and 800 xcexcg of 2, 21.7 xcexcg of 1 and 900 xcexcg of 2, 21.7 xcexcg of 1 and 1000 xcexcg of 2, 24.1 xcexcg of 1 and 25 xcexcg of 2, 24.1 xcexcg of 1 and 50 xcexcg of 2, 24.1 xcexcg of 1 and 100 xcexcg of 2, 24.1 xcexcg of 1 and 200 xcexcg of 2, 24.1 xcexcg of 1 and 300 xcexcg of 2, 24.1 xcexcg of 1 and 400 xcexcg of 2, 24.1 xcexcg of 1 and 500 xcexcg of 2, 24.1 xcexcg of 1 and 600 xcexcg of 2, 24.1 xcexcg of 1 and 700 xcexcg of 2, 24.1 xcexcg of 1 and 800 xcexcg of 2, 24.1 xcexcg of 1 and 900 xcexcg of 2, 24.1 xcexcg of 1 and 1000 xcexcg of 2, 43.3 xcexcg of 1 and 25 xcexcg of 2, 43.3 xcexcg of 1 and 50 xcexcg of 2, 43.3 xcexcg of 1 and 100 xcexcg of 2, 43.3 xcexcg of 1 and 200 xcexcg of 2, 43.3 xcexcg of 1 and 300 xcexcg of 2, 43.3 xcexcg of 1 and 400 xcexcg of 2, 43.3 xcexcg of 1 and 500 xcexcg of 2, 43.3 xcexcg of 1 and 600 xcexcg of 2, 43.3 xcexcg of 1 and 700 xcexcg of 2, 43.3 xcexcg of 1 and 800 xcexcg of 2, 43.3 xcexcg of 1 and 900 xcexcg of 2, 43.3 xcexcg of 1 and 1000 xcexcg of 2, 48.1 xcexcg of 1 and 25 xcexcg of 2, 48.1 xcexcg of 1 and 50 xcexcg of 2, 48.1 xcexcg of 1 and 100 xcexcg of 2, 48.1 xcexcg of 1 and 200 xcexcg of 2, 48.1 xcexcg of 1 and 300 xcexcg of 2, 48.1 xcexcg of 1 and 400 xcexcg of 2, 48.1 xcexcg of 1 and 500 xcexcg of 2, 48.1 xcexcg of 1 and 600 xcexcg of 2, 48.1 xcexcg of 1 and 700 xcexcg of 2, 48.1 xcexcg of 1 and 800 xcexcg of 2, 48.1 xcexcg of 1 and 900 xcexcg of 2, 48.1 xcexcg of 1 and 1000 xcexcg of 2.
If the active substance combination in which 1 is tiotropium bromide monohydrate is used as the preferred combination of 1 and 2 according to the invention, the quantities of 1xe2x80x2 and 2 administered per single dose specified by way of example hereinbefore correspond to the following quantities of 1 and 2 administered per single dose: 6.2 xcexcg of 1 and 25 xcexcg of 2, 6.2 xcexcg of 1 and 50 xcexcg of 2, 6.2 xcexcg of 1 and 100 xcexcg of 2, 6.2 xcexcg of 1 and 200 xcexcg of 2, 6.2 xcexcg of 1 and 300 xcexcg of 2, 6.2 xcexcg of 1 and 400 xcexcg of 2, 6.2 xcexcg of 1 and 500 xcexcg of 2, 6.2 xcexcg of 1 and 600 xcexcg of 2, 6.2 xcexcg of 1 and 700 xcexcg of 2, 6.2 xcexcg of 1 and 800 xcexcg of 2, 6.2 xcexcg of 1 and 900 xcexcg of 2, 6.2 xcexcg of 1 and 1000 xcexcg of 2, 12.5 xcexcg of 1 and 25 xcexcg of 2, 12.5 xcexcg of 1 and 50 xcexcg of 2, 12.5 xcexcg of 1 and 100 xcexcg of 2, 12.5 xcexcg of 1 and 200 xcexcg of 2, 12.5 xcexcg of 1 and 300 xcexcg of 2, 12.5 xcexcg of 1 and 400 xcexcg of 2, 12.5 xcexcg of 1 and 500 xcexcg of 2, 12.5 xcexcg of 1 and 600 xcexcg of 2, 12.5 xcexcg of 1 and 700 xcexcg of 2, 12.5 xcexcg of 1 and 800 xcexcg of 2, 12.5 xcexcg of 1 and 900 xcexcg of 2, 12.5 xcexcg of 1 and 1000 xcexcg of 2, 22.5 xcexcg of 1 and 25 xcexcg of 2, 22.5 xcexcg of 1 and 50 xcexcg of 2, 22.5 xcexcg of 1 and 100 xcexcg of 2, 22.5 xcexcg of 1 and 200 xcexcg of 2, 22.5 xcexcg of 1 and 300 xcexcg of 2, 22.5 xcexcg of 1 and 400 xcexcg of 2, 22.5 xcexcg of 1 and 500 xcexcg of 2, 22.5 xcexcg of 1 and 600 xcexcg of 2, 22.5 xcexcg of 1 and 700 xcexcg of 2, 22.5 xcexcg of 1 and 800 xcexcg of 2, 22.5 xcexcg of 1 and 900 xcexcg of 2, 22.5 xcexcg of 1 and 1000 xcexcg of 2, 25 xcexcg of 1 and 25 xcexcg of 2, 25 xcexcg of 1 and 50 xcexcg of 2, 25 xcexcg of 1 and 100 xcexcg of 2, 25 xcexcg of 1 and 200 xcexcg of 2, 25 xcexcg of 1 and 300 xcexcg of 2, 25 xcexcg of 1 and 400 xcexcg of 2, 25 xcexcg of 1 and 500 xcexcg of 2, 25 xcexcg of 1 and 600 xcexcg of 2, 25 xcexcg of 1 and 700 xcexcg of 2, 25 xcexcg of 1 and 800 xcexcg of 2, 25 xcexcg of 1 and 900 xcexcg of 2, 25 xcexcg of 1 and 1000 xcexcg of 2, 43.3 xcexcg of 1 and 25 xcexcg of 2, 45 xcexcg of 1 and 50 xcexcg of 2, 45 xcexcg of 1 and 100 xcexcg of 2, 45 xcexcg of 1 and 200 xcexcg of 2, 45 xcexcg of 1 and 300 xcexcg of 2, 45 xcexcg of 1 and 400 xcexcg of 2, 45 xcexcg of 1 and 500 xcexcg of 2, 45 xcexcg of 1 and 600 xcexcg of 2, 45 xcexcg of 1 and 700 xcexcg of 2, 45 xcexcg of 1 and 800 xcexcg of 2, 45 xcexcg of 1 and 900 xcexcg of 2, 45 xcexcg of 1 and 1000 xcexcg of 2, 50 xcexcg of 1 and 25 xcexcg of 2, 50 xcexcg of 1 and 50 xcexcg of 2, 50 xcexcg of 1 and 100 xcexcg of 2, 50 xcexcg of 1 and 200 xcexcg of 2, 50 xcexcg of 1 and 300 xcexcg of 2, 50 xcexcg of 1 and 400 xcexcg of 2, 50 xcexcg of 1 and 500 xcexcg of 2, 50 xcexcg of 1 and 600 xcexcg of 2, 50 xcexcg of 1 and 700 xcexcg of 2, 50 xcexcg of 1 and 800 xcexcg of 2, 50 xcexcg of 1 and 900 xcexcg of 2, 50 xcexcg of 1 and 1000 xcexcg of 2.
The active substance combinations of 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1 and 2 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
A) Inhalable Powder Containing the Combinations of Active Substances 1 and 2 According to the Invention
The inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients.
If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250 xcexcm, preferably between 10 and 150 xcexcm, most preferably between 15 and 80 xcexcm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 xcexcm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to 10 xcexcm, more preferably from 1 to 6 xcexcm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.
The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in U.S. Pat. No. 4,570,630A, or by other means as described in DE 36 25 685 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.